The present invention relates to a compound accumulating in inflammatory site, a diagnostic agent containing the compound in labeled state and its precursor compound for labeling. More in detail, the present invention relates to a novel compound having radioactive halogen and properties of accumulation specific to the inflammatory site in vivo in association with a seat of disease including diabetic foot. Also the present invention relates to a diagnostic agent containing said compound in labeled state as the active ingredient which is useful for Nuclear Medicine Diagnosis and its precursor compound for labeling.
Animals including humans bring protecting systems defined as immune response when, for example, subjected to harmful external stimuli. Inflammation reaction is a phenomenon appeared as a part of results of the immune response such as removal of extraneous substances infiltrated into an individual, demolition of invaded tissue and restoration of injured tissue.
A typical phenomenon of such inflammation reaction is also induced in a diabetic foot. A diabetic foot is an ulcer or a destructive lesion of deep tissues caused mainly by an infection, occurring in the lower extremity of a diabetic patient, and is a lesion complicated by neuropathy and various degrees of peripheral blood flow disturbance. The progression of the diabetic foot results in significant consequences in which necrosis occurs in the tissue of the lesion site and the foot needs to be amputated. Thus, it is necessary to detect a diabetic foot early for treatment and to perform an effective treatment while monitoring the efficacy of the treatment.
Leukocytes are included as one of important factors in the inflammation reaction and chemotactic formylated peptides considered to bind to leukocytes through the formylated peptide receptor (hereinafter designated as FPR).
A peptide containing formyl-methionyl-leucyl-phenylalanyl (fMLF), which is a chemotactic formylated peptide, is known as a peptide having affinity for FPR. Also, accumulation of fMLF labeled with a radioactive nuclide is observed in acute inflammation with neutrophils infiltration. Day, A R. et al., FEBS Lett. 77, 291-294 (1977) describes fMLF labeled with the radionuclide 125I. Jiang, M S. et al., Nuklearmedizin, 21, 110-113 (1982) describes that fMLF labeled with the radionuclide 125I accumulates in inflammation in the body. Japanese Patent No. 2931093 discloses 111In fMLF mediated by DTPA (diethylenetriamine pentaacetic acid). Verbeke, K. et al., Nuclear Medicine & Biology, 27, 769-779 (2000) describes Tc-99m fMLF mediated by mercaptoacetylglycylglycine. Baidoo, K. E. et al., Bioconjugate Chemistry, 9, 208-217 (1998) describes Tc-99m fMLF mediated by a diaminodithiol compound. U.S. Pat. No. 4,986,979 describes the use of radionuclide-containing fMLF for in vitro labeling of white blood cells with the radionuclide via the photo-affinity thereof. U.S. Pat. No. 5,792,444 describes fMLF capable of being labeled with a radionuclide. International Publication No. WO 2004/029080 discloses a peptide containing a site for binding to the receptor FPR of white blood cells, a site for enhancing the binding thereof to monocytes and lymphocytes in all white blood cells, and a site capable of being labeled with a radioactive metal.